The invention relates to apolipoprotein E, and in particular to methods of treating disorders relating to ApoE.
Human apolipoprotein (apo) E has three major isoforms, apoE2, apoE3, and apoE4 (for review see Mahley and Huang (1999) Curr. Opin. Lipidol. 10:207-217). It has been established that apoE4 is associated with increased plasma cholesterol levels and higher risk for the development of coronary heart disease. Dallongeville (1992) J. Lipid Res. 33:447-454. ApoE4 has also been linked to the pathogenesis of Alzheimer""s disease. The apoE4 allele is a major risk factor or susceptibility gene associated with approximately 40-65% of cases of sporadic and familial Alzheimer""s disease and it increases the occurrence and lowers the age of onset of the disease. Corder et al. (1993) Science 261:921-923. In addition, the apoE4 allele is also associated with poor clinical outcome in patients with acute head trauma and stroke. Slooter et al. (1997) JAMA 277:818-821; and Nicoll et al. (1996) Neuropathol. Appl. Neurobiol. 22:515-517.
The neuropathological hallmarks of Alzheimer""s disease are the presence of neuritic amyloid plaques and neurofibrillary tangles in the brain. Selkoe (1991) Neuron 6:487-498; and Roses, et al. (1994) Curr. Opinion Biotechnol. 5:663-667. The neuritic plaques represent extracellular deposits of amyloid. The major component of the deposits is the amyloid beta (Axcex2) peptide (DS487), which is the proteolytic product of the amyloid precursor protein (APP). In contrast to amyloid plaques, neurofibrillary tangles are primarily intracellular deposits composed largely of highly phosphorylated microtubule-associated protein, tau (p-tau), and, to a lesser extent, phosphorylated NFxe2x80x94H (p-NFxe2x80x94H). ApoE is found in both amyloid plaques and the neurofibrillary tangles
There are many hypotheses to explain the association of apoE4 allele with the development of Alzheimer""s disease, including its modulation of amyloid xcex2 (Axcex2) deposition or clearance in the brain, and a lack of interaction of apoE4 with the microtubule-associated protein, tau, which binds to and stabilizes microtubules.
Alzheimer""s disease is an insidious and progressive neurological disorder for which there is currently no cure. In view of the lack of adequate treatment for Alzheimer""s disease, there exists a need for novel treatment methods for this neurological disorder. The instant invention provides methods of treating disorders relating to ApoE4, and methods of reducing neurofibrillary tangles associated with Alzheimer""s disease.
Huang et al. (2001) Proc. Natl. Acad. Sci. USA 98:8838-8843; U.S. Pat. No. 6,046,381.
The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.